3-formyl-3alpha-methyl-6-(beta-carboxyethyl)-7-keto-delta2, 5alpha(6)-octahydropentanthrene ester



United States Patent Ofifice 2839567 Patented June 17 1%53 the cyclopentanodimethylpolyhydrophenanthrene series, 2,839,567 r namely a 17-f0rmyl-cyc1opentano-10,13-di1nethyLA U- S-FORMYL-Sa-METHYL 6 (B-CARBOXYETHYL)-7- decahydmphenamhrena"(me KETO A OCTAHYDROPENTANTHRENE 5 EL ESTER Lloyd B. Barkley, Brentwood, Mo., assiguor to Monsanto Chemical Company, St. Louis, Mo., a corporation of I Delaware No Drawing. Applic Serial No. 436,722

ation June 14, 1954 10 I l V i O: 2 Claims. (Cl. 260-468) and methods for making same.

This invention relates to alkyl esters of 1-(/3-carb0xy- 15 The sequence of steps or series of reactions proceeding ethyl) 2 keto 6,7 dihydroxy 14 methyl A to the 17-formy1-cyclopentan0-A -decahydrophenanme and derivatives thereof useful thren-3-one for purposes of this invention is outlined eroids, particularly a member of schematically in the following diagram.

l i if 0: R0OCH2CH2OH:CCH=CH2 H Hi l on OOH: C

I I ocn,

XVI

X VII HPJOH those skilled in the art contains As a result thereof such as will be obvious to two asymmetric carbon atoms. exists in the form of four optically active isomers or two racemates, i. e. cis and trans racemic mixtures of the dextro and levo optically active isomers. All such forms per se or in any combination thereof may be employed in the process outlined herein. The initial reactant (compound I) is prepared by the formylation of the ing 2-keto-10-methyl-1,2,5,8,9,10-hexahydronaphthalene the presence of sodium such is the following:

Example A To a suitable reaction vessel is charged 17.3 parts by weight (substantially 0.32 mol) of solid sodium methylate, 75 parts by weight of anhydrous benzene and 37 (substantially 0.5 mol) of ethyl formate while maintaining the temperature at about 2025 C. The suspension so obtained is then agitated for about 20-30 minutes employing a nitrogen atmosphere and then cooled to about 10 C. Thereupon approximately 16.1 parts by weight (substantially 0.1 mol) of the levorotatory form of trans-Z-keto-lO-methyl-l,2,5,8,9,10-hexahydronaphthalene dissolved in 150 parts by weight of benzene is added and the mixture agitated for about 3 hours at about 15 C. The reaction mass so obtained is then quenched with cold dilute sulfuric acid (20 parts by weight sulfuric acid in 125 parts by weight of water) while maintaining the temperature at about 15 C. and agitating for about minutes. The aqueous layer is separated and extracted with several small portions of benzene. The benzene extracts are combined with the original organic layer and the combined mix subjected to vacuum distillation. The light tan oily residue so obtained consists essentially (95% by weight) of the l-(hydroxy) methylene derivative of the levo-rotatory form of trans-Z-keto- -methyll ,2,5 ,8,9 IO-hexahydronaphthalene. The oil is admixed with 105 parts by weight of methanol and with agitation heated to about 50 C. While constantly agitating 400 parts by weight of an aqueous 5% copper acetate solution is slowly added. The precipitate, namely the copper chelate of the l-(hydroxy) methylene derivative of the levo-rotatory form of trans 2 keto 10 methyl l,2,5,8,9,l0 hexahydronaphthalene, is filtered off, washed with methanol, and then slurried with 87 parts by weight of benzene. To the slurry so obtained is added 1800 parts by weight of 26% sulfuric acid. The organic layer is recovered, washed with aqueous sodium bicarbonate followed by a water wash, and the solvent removed in vacuum. The residue is the oily levo-rotatory isomer of trans-1-(hydroxy) methylene 2 keto 1O methyl 1,2,5,8,9,10 hexa hydronaphthalene, B. P. l22-123 C. at 2-3 mm.

In a similar fashion dl-trans-l-(hydroxy) methylene-2- keto 10 methyl 1,2,5,8,9,10 hexahydronaphthalene is obtained from dl trans- 2 keto 10 methyl 1,2,5 8,9,lO-hexahydronaphthalene. Also, similarly, zil-cis-l- (hydroxy) methylene-2-keto-lO-rnethyl-l ,2,5,8,9,,10-hexa hydronaphthalene is obtained from d! cis 2 keto-10- methyl-1,2,5,8,9,10-hexahydronaphthalene.

In the first step of the process of the foregoing diagram l (hydroxy) methylene 2-keto-l0-methyl-l,2,5,8,9,l0-

correspond- 0 P 3 25 C. for about hexahydronaphthalene is reacted with a 5-keto-6-heptanoic acid ester of the formula 0 ll R0 0 CHaOHnCHtiil CH=OH1 where R is a short chain -'alkyl radical such as methyl, ethyl, propyl, butyl, etc., in an anhydrous media in the presence of a quaternary ammonium alkoxide and an inart solvent such as dioxane, isopropanol, butanol, isobutanol, tert. butanol, pentasol, etc. In general temperatures in the range of 0 to 60 C. can be employed, however, it is preferred that the reaction temperature be about 10 to 30 C. Asillustrative of the preparation of the l-heptanoic acid ester-adduct (compound II) is the following:

Example I To a suitable reaction vessel is added and intimately mixed 14.1 parts by weight of the levo-rotatoiy isomer of trans-l-(hydroxy) methylene 2 keto 10 methyl- 1,2,5,8,9,lO-hexahydronaphthalene, 14.9 parts by weight of 5-keto-6-he'ptenoic acid methyl ester, and 15.6 parts by weight of tort. butanol and the mix cooled to 10-15 C. Thereupon approximately 2.4 parts by weight of a 29.8% by weight n-butanol solution of 'benzyltrimethylammonium n-butoxide admixed with approximately 4 parts by weight of tert. butanol is added to the agitated mixture over a eriod of about 15 minutes. The mix is then held at 20- 16 hours, seeded with a minute amount of the final product and then held at 2025" C. for about 48 hours. To the resultant mass is added with agitation approximately 25 parts by weight of petroleum ether and the mix cooled to about 0 C. The precipitate is filtered ofi, washed with petroleum ether, then with water and dried. The white crystalline product so obtained is the levo-rotatory isomer of trans-l-formyl-l-(3-keto-6-carbomethoxy-hexyl)-2-keto-10-methyl 1,2,5,8,9,10 hexahydronaphthalene of the formula R2 [R1-k-R41 Rs where R R R and R are alkyl or aralkyl radicals and where R is an alkyl radical. Examples of alkyl comprise methyl, ethyl, propyl, butyl, amyl, octyl and the like. Examples of aralkyl comprise benzyl, phenethyl, and the like. The quaternary ammonium alkoxides particularly preferred are those wherein R R and R are straight chain alkyl radicals containing 1-4 carbon atoms, where R; is benzyl and where R is a branched or straight chain alkyl radical containing 2 to 6 carbon atoms.

In the second step of the process described herein the heptanoic acid adduct (compound II) is treated with an alkali metal hydroxide such as sodium or potassium hydroxide and ring closes to form a 1-([3-carboxyethyl)-..-

liGlO 14 methyl-A -octahydrophenanthrene of the formula 0 0 As illustrative of following:

the preparation of such keto-acid is the Example II To a suitable reaction vessel is added and intimately mixed approximately 19 parts by weight of 85% potasapproximately 100 parts by weight of weight of the levorotatory isomer of trans-I-formyl 1 (3-keto-6-carbomethoxy-heXyl)-2-keto l0 methyl1,2,5,8,9,lO-hexahydronaphthalene. This mix so obtained is heated to The crystalline product so obtained is the levo-rotatory isomer of antitrans 1 (,8 carboxyethyl)-2-keto-14-methyl-A octahydrophenanthrene, M. P. 101102 C.,

[a] 3 74 C: 2, CHCI In a similar fashion dl-anti-trans-1-(B-carboxyethyl)-2- keto 14 methyl-A -octahydrophenanthrene is obtained from al-trans-1-formy1-(3-keto 6 7 carbomethoxyhexyl)-2-keto-10-methyl 1,2,5,8,9,10 hexahydronapthalene.

In the third step of the process described herein the carp 7 RO\ where R is a short chain alkyl radical. this step is the following:

As illustrative of Example III To a suitable reaction vessel is added and intimately mixed 100 parts by weight of the levo-rotatory isomer of anti-trans-1-(fi-carboxyethyl)-2-keto-14-methyl A octahydrophenanthrene, 350

yellow oily product identified as the methyl ester of the levo-rotatory isomer of anti-trans-1-(fi-carboxyethyl)-2- keto 14 methyl A octahydrophenanthrene is obtained.

Similarly the methyl ester of dl-anti-trans-1-(,8-carboxyethyl)-2-keto-l4-methyl-A octahydrophenanthrene is obtained from dl-anti-trans-l-(,8-carboxyethyl)-2-keto- 1-4 methyl Mtg-11(1) octahydrophenanthrene and anhydrous methyl alcohol in an acid medium. Other acidic esterification catalysts than hydrochloric acid maybe employed, for example sulfuric acid.

In the fourth step of the process outlined herein the keto-acid ester (compound IV) is converted to the 6,7-

cis-glycol (compound V) I -OH OH R. o 0 0 by treatment of the former with the silver salt of a low molecular weight fatty acid such as acetic acid and bromine or preferably iodine in the presence of a low molecular weight fatty acid such as acetic acid and then hydrolyzing the half'esters so produced. As illustrative of this step is the following:

Example IV 21.6 parts by weight of the methyl ester of the levorotatory isomer of anti-trans-l-(fi-carboxyethyD-Z-keto- 14-methyl-A -octahydrophenanthrene is dissolved parts by Weight of 18.5 parts by we1ght of iodine. To the mix is added 2.5 parts by weight of water and the mix agitated for about 1 hour at 25 C. The mixture is heated to l00 C. and maintained at that temperature for about 3 hours. The reaction mixture is of methyl alcohol and neutralized with potassium hydroxide. To the solution so neutralized is added 209 parts by weight of a 4.5% by weight methanol solution of potassium hydroxide and the mixture allowed to stand for about 16 hours at 25 C. under an atmosphere of nitrogen. The solution is then neutralized with 37% hydrochloric acid and subjected to vacuum distillation. The residue is then taken up The oily residue contains a small amount of the levo-rotatory isomer of anti-trans-l-(B- carboxyethyl) 2-keto-6,7-dihydroxy-14-methyl-A decahydrophenanthrene and principally its methyl ester. The oily residue so obtained is then hydrous methanol and heated in the presence of a small are those obtained from the symmetrical ketones such as acetone, diethyl ketone, cyclohexanone, p-methylcyclohexanone, etc. As illustrative of this step is the follow- 'ing:

Example V 20.8 parts by weight of the methyl ester of the levorotatory isomer of anti-trans-l-(B-carboxyethyl)-2-keto- 6,7 dihydroxy-14-methyl-A -decahydrophenanthrene, 112 parts by weight of anhydrous copper sulfate and 960 parts by weight of dry acetone are intimately mixed at room temperature for about 60 hours. The reaction mass is filtered and the filtrate treated with anhydrous potassium carbonate and filtered and the filtrate subjected to vacuum distillation using a water aspirator. The residue on recrystallization from benzene-petroleum ether yielded white crystalline levo-rotatory isomer of the acetonide of the methyl ester of anti-trans-1([3- carboxyethyl)-2-keto-6,7-dihydroxy 14 methy A decahydrophenanthrene, M. P. 122-124 C., [a] -242.5 (:2, CI-ICl In a similar fashion the acetonide of the methyl ester of dl-anti-trans l (fl-carboxyethyl) 2-keto-6,7-dihydroxy-l4-methyl-A decahydrophenanthrene is obtained from the methyl ester of dl-anti-trans-l-(fl-carboxyethyl) -2-lceto-6,7-dihydroxy-l4-methyl-A decahydrophenanthrene.

In the sixth step of the process outlined herein the 9,10-double bond of the acetonide (compound V1) is selectively reduced in the presence of palladium. The reduction is preferably carried out in a liquid medium, such as an inert organic solvent incapable of hydrogenation under the conditions of the reaction. Examples of such are benzene, toluene, xylene, ethyl benzene, cyclohexane, the liquid alkanes, the lower aliphatic alcohols, etc. As illustrative of this step is the following:

Example VI Approximately 20 parts by weight of the levo-rotatory isomer of the acetonide of the methyl ester of antitrans l-(fi-carboxyethyl) -2-keto-6,7-dihydroxy-14-methyl-A -decahydrophenanthrene is admixed in a suitable reaction vessel with approximately 160 parts by weight of isopropanol, approximately 0.3 part by weight of 10% aqueous sodium hydroxide and 4 parts by weight of a 2% palladium-strontium carbonate catalyst (which had been previously reduced). While agitating, gaseous hydrogen is passed into the mixture at about 25 C. at a pressure slightly above atmospheric. After absorption of substantially one molar equivalent (approximately 0.0535 mol) of hydrogen filtered off and the filtrate neutralized with acetic acid and subjected to vacuum distillation to remove the solvent. The residue is taken up with chloroform, washed with aqueous sodium bicarbonate followed by a water wash, dried over magnesium sulfate, and then evaporated to dryness. The white crystalline product so obtained is the levo-rotatory isomer of the acetonide of the methyl ester of anti-trans-l-(B-carboxyethyl)-l-2-keto-6,7-dihydroxy-l4-methyl-A -dodecahydrophenanthrene, M. P. 106-108" C., [a] =123 (C=2, CHCl In a similar fashion the acetonide of the methyl ester of d l-anti-translfi-carboxyethyl) -2-keto-6,7-dihydroxyl4-methyl-A -dodecahydrophenanthrene is obtained by selectively reducing the acetonide of the methyl ester of dl-anti-trans-l-(B-carboxyethyl)-2-keto-6,7-dihydroxy-14-methyl-A -decahydrophenanthrene employing palladium as the hydrogenation catalyst.

In the seventh step of the process outlined herein the acetonide (compound VII) is hydrolyzed with an acid to the corresponding cis-gly-col (compound VIII), namely the catalyst is preferably not isolated but oxidized (the eighth step of the process outlined herein) to provide the dialdehyde, namely an alkyl ester of l-(fl-carboxyethyl)-2-keto-5,6- di(formylmethyl) 6 methyl A octahydronaphthaicne (compound IX) c11 3 0 2 no As illustrative of the preparation of the alkyl ester of 3 formyl 3a methyl 6 (B carboxyethyl) keto-A -octahydropentanthrene (compound X) from the cyclic acetal the alkyl ester of l-((3carboxyethyl)-2- keto 6,7 dihydroxy 14 methyl A dodecahydrophenanthrenc is the following:

Example VII 9 parts by weight of the levo-rotatory isomer of the acetonide of the methyl ester of anti-trans-l-(/8carboxyethyl) 2 keto 6,7 dihydroxy l4 methyl A dodccahyrophenanthrene is dissolved in approximately 60 parts by weight of acetic acid. Thereupon 60 parts by weight of water is added, intimately mixed and the solution heated on a steam bath for one hour. The solution is cooled to 0-5 C. and approximately 210 parts by weight of water is added. To the solution of the cisglycol so prepared is added at about 05 C. 11.25 parts by weight of lead tetraacctate and 210 parts by weight of acetic acid. The slurry so obtained is agitated for about 10 minutes, and thereafter is added with agitation approximately 100 parts by weight of water. The mixture is then extracted with two 375 parts by weight portions of chloroform. The extracts are combined and washed successively with dilute aqueous sodium bicarbonate, 200 parts by weight of 1N sulfuric acid, dilute aqueous sodium bicarbonate, and finally with water. The so washed solution is dried over magnesium sulfate, filtered and the filtrate subjected to vacuum distillation. The oily residue is the dialdehyde, which is taken up with approximately 1350 parts by weight of anhydrous benzene and heated to C. Thereto is added with agitation approximately 3 parts by weight of acetic acid and approximately 2 parts by weight of piperidine. The

assume? mix so obtained is heated at 70-80 C. for about one hour While passing nitrogen over the mixture and slowly distilling the water-benzene azeotrope. The reaction cessively with dilute hydrochloric acid, dilute sodium bicarbonate and finally with Water. The solution is dried over anhydrous magnesium sulfate and the so dried solution subjected to vacuum distillation. Upon recrystallization of the residue so obtained from diethyl ether, the deXtro-rotatory methyl ester of anti-trans-3-formyl-3amethyl 6 (,8 carboxyethyi) 7 keto A octahydropentanthrene, M. P. 70-72 C., is obtained Similarly the methyl ester of dl-anti-trans-3-formyl- 3a methyl 6 (,8 carboxyethyl) 7 keto A2J5M5) octahydropentanthrene is obtained by the acid hydrolysis of the acetonide of the methyl ester of cll-anti-trans-l- (/3 carboxyethyl) 2 keto 6 .7 dihydroxy 14- rnethyl-A -dodecahydrophenanthrene, cleavage of the glycol so obtained followed by ring closure of the dialdehyde so produced.

In the tenth step of the process outlined herein the 2,3-double bond of the alkyl ester of 3-formyl3a-methyl- 6 9 carboxyethyl) 7 keto A octahydropentanthrene (compound X) is selectively reduced in the presence of palladium to provide the alkyl ester of 3 iformyl 3a methyl 6 (fl carboxyethyl) -7 ketc- A -decahydropentanthrene (compound XI) The reduction is preferably carried out in a liquid medium, such as for example in the presence of an inert organic solvent incapable of hydrogenation under the conditions of the reaction. As illustrative of this step is the following:

Example VIII strontium carbonate (which had been previously reduced). While agitating, gaseous hydrogen is passed into the mixture at about C. at a pressure slightly above atmospheric. After absorption of substantially one molar equivalent (approximately 0.114 mole) of hydrogen, the catalyst is filtered off and the filtrate subjected to vacuum distillation. The oily residue is the dextro-rotatory methy1 ester of anti-trans-3-formyl-3 a-methyl-6-(fi carboxyethyl) 7-keto-A -decahydropentanthrene.

In a similar fashion the methyl ester of dl-anti-trans- 3-formyl-3a-methyl-6-(fi-carboxyethyl)-7-keto-A -decahydropentanthrene is obtained from the methyl ester of cil-anti-trans 3 forrnyl-3a methyl-o-(,B-carboxyethyl) 7- keto-A -octahydropentanthrene employing palladium as the reduction catalyst.

In the eleventhstep of the process outlined herein the monoethylene ketal, namely an alkyl ester of 3-[2-(l,3- dioxacyclopentanyl)]-3a-methyl-6 3 carboxyethyl)-7- .ketO-M -decahydropentanthrene (compound XII) is prepared by condensing an alkyl ester of 3-formyl-3amethyl-6- (p-carboxyethyl) 7-keto-A decahydropentanthrene with an equimolecularamount of ethylene glycol if) in the presence of an acid condensation catalyst. As illustrative of this process step is the following:

Example IX Approximately 35 parts by weight of the dextro-rotatory isomer of the methyl ester of anti-trans-3-formyl-3amethyl-6- (fl carboxyethyl)-7-keto-A a decahydropentanthrene of Example VIII is dissolved in mixture of about mass is brought to reflux and the benzene-water azeotrope the mass is subjected to vacuum distillation to remove the solvent. The residue is taken up with chloroform, and the chloroform solu- CHQO In asiniilar fashion the methyl ester of 'dl-anti-trans 3-[2-(l,3-dioxacyclopentanyl)J-3a-methyl-6-(B carboxyethyl)-7 keto-A -decahydropentanthrene is obtained upon condensing ethylene glycol with the methyl ester of zil-anti-trans 3 formyl-B-aunethyl-b-(fl-carboxyethyl)-7- keto-A -decahydropentanthrene in the presence of an acid condensation catalyst.

In the twelfth like methylating agents such tosylate, etc., with the alkyl ester of 3-[2-(1,3-dioxacyclopentanyl)]-3a-methyl-6-(fi-carboxyethyl)-7 keto M decahydropentanthrene (compound XII). In the intro- Although both of the isomeric aconverted to a tetracyclic ketonc of compounds XV, XVI and forth hereinbefore the ,B-keto and fi-keto acids may be of the general structure XVII of the diagram set acid as identified herein arated form. In general, however,

hydropentanthrene (compound XIII) and conversion to the free acid (compound XIV) is the following:

Example X 12.22 parts by weight of the mono-ethylene ketal of the optically active methyl ester of anti-trans-3-formyl- 3a-m'ethyl-6-(B-carboxyethyl) -7-keto A decahydropentanthrene of Example IX is dissolved in a mixture of about 360 parts by weight of benzene and about 320 parts by weight of tert. butanol. Thereto is added and intimately mixed 285 parts by weight of 0.467 N potassium tert. butoxide in tert. butanol. While refluxing the mixture approximately 41 parts by weight of methyl iodide is cautiously added. Upon completion of the methyl iodide addition the reaction mass is refluxed for about 5 minutes. The mix is cooled to room temperature. This solution which contains the respective methyl esters of the aand B-anti-trans-keto acids in a weight ratio of approximately 1 to 2 is admixed with 200 parts by weight of water in order to hydrolyze the esters. The organic layer is separated and extracted with dilute aqueous potassium hydroxide. The organic layer is separated and cooled to about 5 (3., admixed with an equal volume of diethyl ether and the mix then acidified with dilute sulfuric acid. The aqueous layer is removed and extracted with two equal volumes of diethyl ether. The ether extracts are combined, washed with water and dried. Upon removal of the ether by vacuum distillation approximately 11.96 parts by weight of an oil consisting of the a and 13 isomers of the respective keto-acids in weight ratio of approximately 1 to 2 is obtained.

If desired the oily mixture of ocand fi-keto acids may be separated into its component parts by various well known methods. As for example by dissolving the oil in a low molecular weight alkanol such as methanol, admixing therewith a chemically equivalent weight of quinine, and refluxing the reaction mass. Upon cooling to room temperature or below the respective quinine salts may be effectively separated by fractional crystallization. The respective quinine salts on treatment with an alkaline material more basic than quinine in an aqueous medium, followed by separating the free quinine by filtration, and subsequently acidifying with mineral acid yields the respective aand B-keto acids in septhe mixture is not separated into its component keto-acid isomeric parts but boiled (step fourteen of the process outlined herein) with acetic anhydride in the presence of a small amount of sodium acetate. By so doing the enol lactone (compound XV), e. g. 3-keto-17-[2-(1,3-dioxacyclopentanyl)] cyclopentano 10,13 dimethyl A -4 oxadecahydrophenanthrene, is obtained as a mixture of isomers which may be represented structurally and defined as follows:

5 0011: 3 0 CH: oon. 1: oi:rn

O a-Euo1 lactone fl-Euol lactone The solution is washed As illustrative of this step is the following:

Example XI 11.96 parts by weight of the oily mixture of keto-acids obtained in Example X is dissolved in 162 parts by weight of acetic anhydride containing 0.1 part by weight of sodium acetate and refluxed for four hours under an atmosphere of nitrogen. The reaction mass is then cooled. The acetic anhydride is removed by vacuum distillation and the residue taken up with diethyl ether. with aqueous sodium bicarbonate, wash and dried. Upon removal of distillation an oil is obtained which The weight yield is 9.95 parts and B-enol lactones in followed by a water the ether by vacuum on standing crystallized. by weight of a mixture of aabout a 1 to 2 weight ratio.

In the fifteenth step of the process outlined herein the enol lactone (compound XV) is converted to the corresponding tetracyclic ketone (compound XVI), i. e. the mono-ethylene ketal of 3-keto-l7-formyl-cyclopentano-10,13dimethyl-A -decahydrophenanthrene, by reacting the former with a methyl magnesium halide in diethyl ether, decomposing the addition product with mineral acid, and then treating the ether solubles with an alcohol solution of an alkali metal hydroxide. This step affords the means for conveniently separating the unwanted stereoisomer from the desired stereoisomer and as illustrative thereof is the following:

Example XII 9.95 parts byweight of the crystalline mixture of aand fl-enol lactones of Example XI is dissolved in mixture of about 500 parts by weight diethyl ether and about 175 parts by weight of benzene and cooled to about -50 C. Thereto is added with agitation an ether solution containing 4.25 parts by weight of methyl magnesium bromide while maintaining the temperature below -50 C. Upon completion of the methyl magnesium bromide addition the mix is stirred at -50 to 55 C. for about minutes. Thereafter approximately 50 parts by weight of acetone, approximately 60 parts by weight of water and approximately 20 parts by weight of acetic acid is added and intimately mixed and the mix permitted to rise to about 0 C. The layers are separated and the ether extract washed with aqueous sodium carbonate, water washed, dried and subjected to vacuum distillation. The oily residue is taken up with 400 parts by weight of methyl alcohol and thereto is added 72 parts by weight of 16.7% aqueous solution of potassium hydroxide and the mixture so obtained refluxed for about 2 hours under a nitrogen atmosphere. Thereupon substantially all of the methanol is removed by vacuum distillation. An equal volume of water is added to the residue, and the resultant mix extracted twice with equal volumes of chloroform. The extracts are combined, dried and subjected to vacuum distillation. Approximately 6.51 parts by weight of an oily residue which partially crystallized on standing is obtained. The residue is dissolved in methanol and set aside to permit crystallization. Upon filtration white crystals of the optically active mono-ethylene ketal of 1 -21-norprogesterone, M. P. 172-175 C.

is obtained.

In a similar manner the mono-ethylene ketal of white crystalline dl-A -ZI-norprogesterone is obtained by proceeding through the processes set forth in Examples X and XI beginning with the alkyl ester of dl-anti-trans- 3 [2 (1,3 dioxacyclopentanyl)l 3a methyl 6 (p-carboxyethyl) -7-keto-A -decahydropentanthrene.

In the sixteenth step of the process outlined herein the mono-ethylene ketal (compound XVI) is converte to the corresponding 17-formyl-cyclopentano-l0,l3 dimethyl A decahydrophenanthrene 3 one (compound XVII) by heating the former in the presence of an acid. As illustrative of such is the following:

Example XIII parts by Weight of the mono-ethylene ketal obtained by the process of Example XI is heated with 5000 parts by weight of 50% aqueous acetic acid at 100 C. for approximately 90 minutes. The reaction mass is subjected to vacuum distillation and the residue taken up crystalline dextro-rotatory isomer of A -21-norprogesterone, M. P. 127-131 C.

Similarly all-A -21-norprogesterone is obtained from the mono-ethylene ketal of dl-A -21-norprogesterone. The compound of Example XII so obtained is identical hydrogen with the dextro-rotatory isomer of N -21- norprogesterone (M. P. 160.5161.5 C.) in the presfor the dextr -rotatory isomer of M -progesterone.

While this invention has been described with respect departing from the spirit or scope of the invention. For example, 1 (p carboxyethyl) 2 keto 6,7 dihydroxy l4- methyl A110) dodecahydrophenanthrene alkyl ester (compound VIII) may be obtained directly from the corresponding alkyl ester of l-(B-carboxyethyh- 2 keto 6,7 dihydroxy 14 methyl A -decahywhich dialdehyde is dissolved in an aromatic hydrocarbon solvent and cyclized employing piperidine acetate to provide the corresponding alkyl ester of 3-formyl-3a-methyl- 6 (,8 carboxyethyl) 7 keto A hexahydropentanthrene which compound upon reacting with two equimolecular proportions of hydrogen in the presence of palladium yields the corresponding alkyl ester of 3-formyl-3a-methyl 6 ([3 carboxyethyl) 7 keto A5146) decahydropentanthrene.

Compounds of the structural formula of that of compound II of the foregoing diagram are claimed in copending application Serial No. 436,721, filed of even date, of Martin W. Farrar.

Compounds of the structural formulae of that of compounds III and IV of the foregoing diagram are claimed date, of Harold Raffelson.

What is claimed is:

1. The dextro-rotatory isomer of an alkyl ester of anti-trans 3 formyl 3a methy 6 (B carboxyethyl)-7-keto-A -octahydropentanthrene wherein said 7 alkyl radical is a short chain alkyl radical.

2. The dextro-rotatory isomer of the methyl ester of anti-trans 3 formyl 3a methyl 6 3 carboxyethyl)-7-keto-A -octahydropentanthrene.

References Cited in the file of this patent UNITED STATES PATENTS Woodward Mar. 16, 1954 OTHER REFERENCES Woodward et al.: J. Am. Chem. Soc. 74, 4231, 4247 (1952). 

1. THE DEXTRO-ROTATORY ISOMER OF AN ALKYL ESTER OF ANTI-TRANS -3- FORMYL - 3A METHYL - 6 - (6-CARBOXYETHYL)-7-KETO-$2,5A(6)-OCTAHYDROPENTANTHRENE WHEREIN SAID ALKYL RADICAL IS A SHORT CHAIN ALKYL RADICAL. 